Preparation of 5-(hydroxy- and/or aminophenyl-6-lower-alkyl)-2(1H)-pyridinones

ABSTRACT

Disclosed and claimed is the cardiotonic use of 1-R 1  -5-(3-R&#39;-4-R&#34;-phenyl)-6-R-2(1H)-pyridinones (II), where R 1  is hydrogen, lower-alkyl or lower-hydroxyalkyl, R is lower-alkyl or hydrogen, and, R&#39; and R&#34; are each hydrogen, amino or hydroxy, at least one of R&#39; or R&#34; being other than hydrogen, or where R&#39; is nitro when R&#34; is hydroxy, or pharmaceutically acceptable acid-addition salts thereof where at least one of R&#39; and R&#34; is amino. Also disclosed and claimed are 1-R 1  -5-(3-R&#39;-4-R&#34;-phenyl)-6-R-2(1H)-pyridinones (I), where R 1 , R&#39; and R&#34; are defined as above and R is lower-alkyl and acid-addition salts thereof where at least one of R&#39; and R&#34; is amino. Also shown and claimed is the process which comprises reacting 1-R 1  -1,2-dihydro-2-oxo-5-(3-R&#39;-4-R&#34;-phenyl)-6-R-nicotinonitrile, where R 1  and R are defined as above for II, R&#39; is hydrogen, hydroxy, methoxy or amino and R&#34; is hydroxy, methoxy or hydrogen, preferably at least one of R&#39; and R&#34; being methoxy, or where R&#39; is nitro and R&#34; is hydrogen or methoxy, preferably methoxy, with 85% phosphoric acid to produce 1-R 1  -5-(3-R&#39;-4-R&#34;-phenyl)-6-R-2(1H)-pyridinone, where R 1  and R are defined as above for II, R&#39; is hydrogen, hydroxy or amino and R&#34; is hydroxy or hydrogen, at least one of R&#39; and R&#34; being hydroxy, or where R&#39; is nitro and R&#34; is hydroxy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of copending U.S. patent appplicationSer. No. 372,174, filed Apr. 26, 1982, now U.S. Pat. No. 4,465,686,issued Aug. 14, 1984, which in turn is a continuation-in-part ofcopending U.S. patent application Ser. No. 300,294, filed Sept. 8, 1981and now abandoned.

The 1-R₁ -1,2-dihydro-2-oxo-5-(substituted-phenyl)-6-R-nicotinonitriles,used herein as intermediates, are disclosed as cardiotonic agents and asintermediates for preparing the corresponding 3-amino-1-R₁-5-(substituted-phenyl)-6-R-2(1H)-pyridinones and are claimed incopending Lesher, Opalka and Page U.S. patent application Ser. No.355,229, filed Mar. 5, 1982, now U.S. Pat. No. 4,515,797, issued May 7,1985 as a continuation-in-part of its copending U.S. patent applicationsSer. No's. 300,294, filed Sept. 8, 1981 and now abandoned and 348,450,filed Feb. 12, 1982 and now abandoned, the latter as acontinuation-in-part of its copending U.S. patent application Ser. No.248,840, filed Mar. 30, 1981 and now abandoned.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 5-(substituted-phenyl)-2(1H)-pyridinones,their preparation and their use as cardiotonics.

(b) Description of the Prior Art

Julia et al., Bull. soc. chim. (France), 2387-2394 (1966), show interalia the reaction of 1-hydroxymethylene-1-phenyl-2-propanone withα-cyanoacetamide to produce2-hydroxy-5-(unsubstituted-phenyl)-6-methylnicotinonitrile and thereaction of 3-dimethylamino-2-phenyl-2-propenal (same asβ-dimethylamino-α-phenylacrolein) with α-cyanoacetamide to produce2-hydroxy-5-(unsubstituted-phenyl)nicotinonitrile. These 2-hydroxycompounds, tautomers of the corresponding 1,2-dihydro-2(1H)-pyridinones,were converted to their corresponding carboxylic acids and ethyl ormethyl esters and also to their 2-chloro compounds and5-(unsubstituted-phenyl)-3-piperidinecarboxamide derivatives,representative members of which were found to have pharmacologicalactivity resembling that of lysergamide.

Shen et al. U.S. Pat. No. 3,718,743, issued Feb. 27, 1973, shows"5-phenyl-2-piperidinones and 5-phenyl-2-thiopiperidinones incompositions and methods for treating pain, fever and inflammation". Thegeneric teaching of these piperidinones shows that "phenyl" can have oneor two substituents at positions 2, 3, 4, 5 and/or 6, e.g., inter alia,nitro, amino, lower-alkyl, lower alkylamino and lower-alkylmercapto.Various means of preparing the 5-phenyl-2-piperidinone final productsare shown. In one procedure, a 2-chloro-5-phenylpyridine was heated withaqueous sodium hydroxide in dimethylformamide to produce thecorresponding 5-phenyl-2(1H)-pyridinones which were then hydrogenated toproduce the desired 5-phenyl-2-piperidinones. Among the5-phenyl-2(1H)-pyridinones specifically shown is5-(4-hydroxyphenyl)-2(1H)-pyridinone and its preparation by heating thecorresponding 5-(4-methoxyphenyl)-2(1H)-pyridinone with pyridinehydrochloride under nitrogen. The only use shown for said5-(4-hyroxyphenyl)2(1H)-pyridinone is as an intermediate.

Shen et al U.S. Pat. Nos. 3,655,679, issued Apr. 11, 1972, and3,703,582, issued Nov. 21, 1972, show as antiinflammatory, analgesic andantipyretic agents various aryl-hydroxy-pyridinecarboxylic acids andlower-alkyl esters thereof, among which are5-(substituted-phenyl)-2-hydroxynicotinic acid. These latter compoundswere prepared by reacting a2-(substituted-phenyl)-3-dimethylamino-2-propenal with cyanoacetamide tofirst produce 5-(substituted-phenyl)-2-hydroxynicotinonitrile,illustrated inter alia by the compounds where substituted-phenyl is4-chlorophenyl, 3,4-dihydroxyphenyl, 4-nitrophenyl, 4-benzoylaminophenyland 2,6-dimethoxyphenyl. Also shown is the preparation of thecorresponding 2-hydroxy-6-methyl-5-(substituted-phenyl)nicotinonitrileby reacting 2-(substituted-phenyl)-acetoacetaldehyde with cyanoacetamidefollowed by hydrolysis of the nicotinonitrile to the correspondingnicotinic acid. Illustrations of intermediate nicotinonitriles producedby this procedure include inter alia the compounds wheresubstituted-phenyl is 2-hydroxyphenyl, 4-methoxyphenyl and4-aminophenyl.

Lesher and Opalka [U.S. Pat. Nos. 4,004,012, issued Jan. 18, 1977, and4,072,746, issued Feb. 7, 1978]show as cardiotonic agents 3-amino(orcyano)-5-(pyridinyl)-2(1H)-pyridinones. A preferred embodiment of thesecompounds is 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, now genericallyknown as amrinone and alternatively named5-amino-[3,4'-bipyridin]-6(1H)-one. One method shown for preparing the3-cyano-5-(pyridinyl)-2(1H)-pyridinones, alternatively named1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitriles, is the reaction ofα-(pyridinyl)-β-(dialkylamino)acrolein with α-cyanoacetamide. U.S. Pat.No. 4,072,746 also shows inter alia, 3-Q-5-(pyridinyl)-2(1H)-pyridinoneswhere Q is hydrogen. The disclosure of U.S. Pat. No. 4,072,746 also isshown in Lesher and Opalka U.S. Pat. Nos. 4,107,315, 4,137,233,4,199,586 and 4,225,715.

Lesher, Opalka and Page U.S. Pat. No. 4,276,293, issued June 30, 1981,shows inter alia1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles byreacting a 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketonewith α-cyanoacetamide and the conversion, by hydrolysis anddecarboxylation, of said nicotinonitriles to the corresponding6-(lower-alkyl)-5-(pyridinyl)-2(1H-pyridinones.

Lesher and Philion pending U.S. patent application Ser. No. 198,461,filed Oct. 20, 1980 and now U.S. Pat. No. 4,313,951, issued Feb. 2,1982, a continuation-in-part of application Ser. No. 97,504, filed Nov.26, 1979 and now abandoned, discloses and claims as cardiotonics, interalia, 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitrilesand their preparation.

Lesher, Opalka and Page U.S. patent application Ser. No. 204,726, filedNov. 6, 1980 and now U.S. Pat. No. 4,312,875, issued Jan. 26, 1982, acontinuation-in-part of U.S. application Ser. No. 135,100, filed Mar.28, 1980 and now U.S. Pat. No. 4,297,360, issued Oct. 27, 1981,discloses and claims as cardiotonics,6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.

Lesher and Singh U.S. Pat. No. 4,297,362, issued Oct. 27, 1981, shows4-(3,4-diaminophenyl)pyridine or salt and its cardiotonic use.

Collins, Lesher and Singh U.S. Pat. No. 4,302,462, issued Nov. 24, 1981,shows 4-(4- or 3-pyridinyl)-1,2-benzenediol or salt and dimethyl ethersthereof as cardiotonic agents.

(c) Prior Publications

Alousi et al, Fed. Proc., Pt. I, Abstracts, item 2478, page 663, Mar. 1,1981 (65th Annual Meeting, Atlanta, Ga., Apr. 12-17, 1981), show1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, also named1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile, to be moreactive than amrinone, namely, 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone.

The following publications appeared prior to the filing of the instantapplication but subsequent the filing of parent application Ser. No.300,294 and subsequent to completion of applicants' invention disclosedand claimed herein: Sandoz AG Patent Cooperation Treaty Application No.81/02575, published Sept. 17, 1981, and corresponding U.K. PatentApplications No. 2,070,606, published Sept. 9, 1981, which disclose,inter alia, as cardiotonic agents and claim selected 3-amino-6-R₂-5-aryl-2(1H)-pyridinones where R₂ is hydrogen or lower-alkyl and arylis, inter alia, phenyl, 4-methoxyphenyl, 3-methoxyphenyl or3,4-dimethoxyphenyl. These compounds are reportedly prepared from thecorresponding 1,2-dihydro-2-oxo-6-R₂ -5-arylnicotinamides, in turn,prepared from the corresponding 1,2-dihydro-2-oxo-6-R₂-5-arylnicotinonitriles.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention resides in 1-R₁ -5-[3-and/or 4-(hydroxy and/or amino)-phenyl or4-hydroxy-3-nitrophenyl]-6-(lower-alkyl)-2(1H)-pyridinones (I) andsalts, useful as cardiotonic agents, where R₁ is hydrogen, lower-alkylor lower-hydroxyalkyl.

A composition aspect of the invention resides in the cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier, and as the activecomponent thereof, a cardiotonically-effective amount of 1-R₁-5-[3-and/or 4-(hydroxy and/or amino)phenyl or4-hydroxy-3-nitrophenyl]-6-R-2(1H)-pyridinone (II) or salt thereof,where R₁ is defined as above and R is hydrogen or lower-alkyl.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering a medicament comprising a pharmaceuticallyacceptable carrier and, as the active component, a cardiotonicallyeffective amount of 1-R₁ -5-[3- and/or 4-(hydroxy and/or amino)phenyl or4-hydroxy-3-nitrophenyl]-6-R-2(1H)-pyridinone (II) or salt thereof,where R and R₁ are defined as above.

In a process aspect the invention resides in the process for preparing1-R₁ -5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone, where R₁ and R aredefined as above, R' is hydrogen, hydroxy or amino and R" is hydroxy orhydrogen or where R' is nitro when R" is hydroxy, at least one of R' andR" being hydroxy, which comprises reacting a 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile, where R₁and R are defined as above, R' is hydrogen, hydroxy, methoxy or aminoand R" is hydroxy, methoxy or hydrogen, preferably at least one of R'and R" being methoxy, or where R' is nitro when R" is hydroxy ormethoxy, preferably methoxy, with 85% phosphoric acid.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

A composition of matter aspect of the invention resides in a 1-R₁-5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone having formula I ##STR1##where R₁ is hydrogen, lower-alkyl or lower-hydroxyalkyl, R islower-alkyl, R' and R" are each hydrogen, amino or hydroxy, at least oneof R' or R" being other than hydrogen, or where R' is nitro and R" ishydroxy; or an acid-addition salt thereof where at least one of R' andR" is amino. The compounds of formula I are useful as cardiotonics, asdetermined by standard pharmacological evaluation procedures. Preferredembodiments are those of formula I where R₁ is hydrogen, R is methyl orethyl, R' is hydrogen, hydroxy or amino and R" is hydroxy or hydrogen,the latter only when R' is other than hydrogen. Particularly preferredembodiments are the compounds of formula I where R is methyl, R₁ ishydrogen, and one of or both R" and R' represent hydroxy or R' is aminoand R" is hydroxy.

A composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier and, as the activecomponent thereof, a cardiotonically effective amount of 1-R₁-5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone having formula II ##STR2##where R₁, R' and R" have the above-given definitions of formula I and Ris hydrogen or lower-alkyl; or pharmaceutically acceptable acid-additionsalt thereof where at least one of R' and R" is amino. Preferredembodiments of this composition aspect of the invention are those wherethe active component is the compound of formula II where R₁ is hydrogen,R is hydrogen, methyl or ethyl, R' is hydrogen, hydroxy or amino, and R"is hydroxy or hydrogen the latter only when R' is other than hydrogen.Particularly preferred embodiments are those where the active componentis the compound of formula II where R is methyl, R₁ is hydrogen and oneor both R" and R' represent hydroxy or R' is amino and R" is hydroxy.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient a composition comprising a pharmaceuticallyacceptable carrier and, as active component thereof, a cardiotonicallyeffective amount of 1-R₁ -5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone offormula II hereinabove where R₁, R' and R" have the previously givenmeanings and R is hydrogen or lower-alkyl; or pharmaceuticallyacceptable salt thereof where at least one of R' and R" is amino.Preferred and particularly preferred embodiments of this method aspectof the invention are those where the active component is the same as theactive component of the respective preferred and particularly preferredcomposition embodiments described in the immediately precedingparagraph.

A process aspect of the invention resides in the process which comprisesreacting a 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile, where R₁and R are defined as in formula II, R' is hydrogen, hydroxy, methoxy oramino and R" is hydroxy, methoxy or hydrogen, preferably at least one ofR' and R" being methoxy, or where R' is nitro when R" is hydroxy ormethoxy, preferably methoxy, with 85% phosphoric acid to produce 1-R₁-5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone, where R₁ and R have themeanings given above, R' is hydrogen, hydroxy or amino and R" is hydroxyor hydrogen, at least one of R' and R" being hydroxy, or where R' isnitro when R" is hydroxy. In the preferred embodiments of this processaspect, the intermediate substituted-nicotinonitriles where at least oneof R' and R" is methoxy undergo several conversions to produce the finalproducts, namely, cleavage of the methoxyphenyl or dimethoxyphenylethers to produce the corresponding hydroxyphenyl or dihydroxyphenylmoieties, to hydrolyze the nitrile to the corresponding carboxylic acidand to decarboxylate said acid.

The term "lower-alkyl" as used herein, e.g., as one of the meanings of Rand R₁, means alkyl radicals having from one to six carbon atoms whichcan be arranged as straight or branched chains, illustrated by methyl,ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl,n-amyl, n-hexyl, and the like.

The term "lower-hydroxyalkyl", as used herein, e.g., as one of themeanings for R₁ in formula I, means a hydroxyalkyl radical having fromtwo to six carbon atoms and having its hydroxy group and its freevalence bond (or connecting linkage) on different carbon atoms which canbe arranged as straight or branched chains, illustrated by2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl,5-hydroxyamyl, 6-hydroxyhexyl, and the like.

The compounds of the invention having formula I or II in which at leastone of R' and R" is amino are useful both in the free base and in theform of acid-addition salts, and both forms are within the purview ofthe invention. The acid-addition salts are simply a more convenient formfor use; and in practice, use of the salt form inherently amounts to useof the base form. The acids which can be used to prepare theacid-addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are relatively innocuous to the animal organism inpharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base form of the cardiotonically activecompounds of the invention are not vitiated by side effects ascribableto the anions. In practicing the invention, it is convenient to use thefree base form; however, appropriate pharmaceutically acceptable saltswithin the scope of the invention are those derived from mineral acidssuch as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamicacid; and organic acids such as acetic acid, citric acid, lactic acid,tartaric acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid,quinic acid, and the like, giving the hydrochloride, sulfate, phosphate,sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solution or othersuitable solvents containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

Although pharmaceutically acceptable salts of said basic compounds arepreferred, all acid-addition salts are within the scope of ourinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically acceptable salt by ionexchange procedures.

The molecular structures of the compounds of the invention were assignedon the basis of evidence provided by infrared, nuclear magneticresonance and mass spectra, and by the correspondence of calculated andfound values for the elemental analyses.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same.

The reaction of 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile, where R₁and R are defined as in formula II, R' is hydrogen, hydroxy, methoxy oramino and R" is hydroxy, methoxy or hydrogen, preferably at least one ofR' and R" being methoxy, or where R' is nitro when R" is hydroxy ormethoxy, with 85% phosphoric acid to produce 1-R₁-5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone, where R₁ and R have themeanings given above, R' is hydrogen, hydroxy or amino and R" is hydroxyor hydrogen, at least one of R' and R" being hydroxy, or where R' isnitro when R" is hydroxy, is carried out by heating the reactants,preferably refluxing the reaction mixture.

The above intermediate 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile where R₁ isdefined as in formula II, R is lower-alkyl, R' is hydrogen, hydroxy,methoxy or amino and R" is hydroxy, methoxy or hydrogen, or where R' isnitro when R" is hydroxy or methoxy, is prepared by reacting1-(3-R'-4-R"-phenyl)-2-(dimethylamino)ethenyl lower-alkyl ketone withN-R₁ -α-cyanoacetamide. This reaction is carried out preferably byheating the reactants in a suitable solvent in the presence of a basiccondensing agent. The reaction is conveniently run using an alkali metallower-alkoxide, preferably sodium methoxide or ethoxide, indimethylformamide. In practicing the invention, the reaction was carriedout in refluxing dimethylformamide using sodium methoxide.Alternatively, methanol and sodium methoxide or ethanol and sodiumethoxide can be used as solvent and basic condensing agent,respectively; however, a longer heating period is required. Other basiccondensing agents and solvents include sodium hydride, lithiumdiethylamide, lithium diisopropylamide, and the like, in an aproticsolvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene, dioxane,and the like. Alternatively, the intermediate nicotinonitriles compoundswhere R' and/or R" represent hydroxy and/or amino can be prepared byfirst preparing the corresponding compound where R' and/or R" representrespectively, methoxy and/or nitro, which in turn is then reacted with areagent capable of converting methoxy to hydroxy and/or with a reagentcapable of converting nitro to amino.

The above intermediate 1-(3-R'-4-R"-phenyl)-2-(dimethylamino)ethenyllower-alkyl ketone is prepared by reacting 3-R'-4-R"-benzyl lower-alkylketone with dimethylformamide di-(lower-alkyl) acetal. This reaction iscarried out by mixing the reactants neat or in the presence of asuitable solvent The reaction is conveniently run at room temperature,i.e., about 20°-25° C., or by warming the reactants to about 100° C.,preferably in an aprotic solvent, preferably dimethylformamide. Othersuitable solvents include tetrahydrofuran, acetonitrile, ether, benzene,dioxane, and the like. Alternatively, the reaction can be run using nosolvent, using an excess of dimethylformamide di-(lower-alkyl)acetal.

The intermediate 3-R'-4-R"-benzyl lower-alkyl ketones (II) are generallyknown compounds which are prepared by known methods, e.g., Beilstein 8,87, 102, 103, 280 (1925); ibid. 14, 59 (1931).

The intermediate 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile where R₁ isdefined as in formula II, R is hydrogen, R' is hydrogen, hydroxy,methoxy or amino and R" is hydroxy, methoxy or hydrogen, is prepared bythe generally known procedure of reacting the appropriate2-(substituted-phenyl)-3-dimethylamino-2-propenal with N-R₁-cyanoacetamide, as shown in said Shen et al U.S. Pat. Nos. 3,655,679and 3,703,582.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 1-R₁ -1,2-DIHYDRO-2-OXO-5-(SUBSTITUTED-PHENYL)-6-R-NICOTINONITRILES

A-1. 1,2-Dihydro-5-(4-methoxyphenyl)-2-oxonicotinonitrile--To a stirredmixture containing 13.5 g. of sodium methoxide in 200 ml. of methanolwas added 12.61 g. of cyanoacetamide and 20.5 g. of3-dimethylamino-2-(4-methoxyphenyl)-2-propenal and the resulting mixturewas heated with stirring on a steam bath for 12 hours. The reactionmixture was concentrated in vacuo to yield a yellow semi-solid material.This material was suspended in water and the resulting mixture (partialdissolution) was acidified with acetic acid. The separated solid wascollected, washed with water, dried in vacuo, recrystallized fromdimethylformamide and dried in vacuo for 24 hours at 0.01 mm. and 80° C.to produce 11.6 g. of1,2-dihydro-5-(4-methoxyphenyl)-2-oxonicotinonitrile, m.p. 294°-295° C.with decomposition.

The intermediate 3-dimethylamino-2-(4-methoxyphenyl)-2-propenal wasprepared by the procedure described below in the second paragraphfollowing Example A-11 but using α-(4-methoxyphenyl)acetic acid in placeof α-(3,4-dimethoxyphenyl)acetic acid.

A-2. 1,2-Dihydro-5-(4-hydroxyphenyl)-2-oxonicotinonitrile--To a mixturecontaining 11.3 g. of1,2-dihydro-5-(4-methoxyphenyl)-2-oxonicotinonitrile in 110 ml. ofcollidine was added 36.8 g. of anhydrous lithium iodide and theresulting mixture was refluxed with stirring under nitrogen for 24hours. The reaction mixture was cooled, treated with ice and acidifiedwith 6N hydrochloric acid and cooled. The precipitated solid wascollected and dried in vacuo to yield 8.5 g. of1,2-dihydro-5-(4-hydroxyphenyl)-2-oxonicotinonitrile. The productobtained herein was combined with another sample obtained by comparablerun and the combined material was recrystallized fromdimethylformamide-methanol and dried at 0.01 mm and 100° C. for 7 daysto produce 13.47 g. of1,2-dihydro-5-(4-hydroxyphenyl)-2-oxonicotinonitrile, m.p. >300° C.

A-3. 1,2-Dihydro-5-(4-nitrophenyl)-2-oxonicotinonitrile, m.p. 339°-346°C. with decomposition, 87.2 g., was obtained following the proceduredescribed in Example A-1 using 83 g. of3-dimethylamino-2-(4-nitrophenyl)-2-propenal, 50.4 g. of cyanoacetamide,54 g. of sodium methoxide and 1500 ml. of methanol.

A-4. 5-(4-Aminophenyl)-1,2-dihydro-2-oxonicotinonitrile--A mixturecontaining 14.47 g. of1,2-dihydro-5-(4-nitrophenyl)-2-oxonicotinonitrile, 1.0 g. of 10%palladium-on-charcoal, 300 ml. of dimethylformamide and 5.76 g. of (3.9ml.) of methanesulfonic acid was treated under catalytic hydrogenationconditions until the theoretical quantity of hydrogen to reduce nitro toamino was taken up. The reaction mixture was filtered throughdiatomaceous earth to remove the catalyst. The filtrate was concentratedin vacuo to a volume of about 200 ml. and to the concentrate was addedslowly 3.9 ml. (5.76 g.) of methanesulfonic acid, the mixture stirredfor about 10 minutes and then treated with about 500 ml. of methylenedichloride. The crystalline solid was collected, dissolved in about 900ml. of hot methanol, the hot solution treated with decolorizing charcoaland then filtered through a sintered glass funnel. The filtrate wascooled and the separated crystalline material was collected andrecrystallized from methanol. The resulting product was dissolved in 150ml. of warm 2N hydrochloric acid, the solution basified with aqueoussodium hydroxide solution and cooled. The resulting white solid wascollected, dissolved in 400 ml. of methanol, treated with 2 ml. ofmethanesulfonic acid, the mixture concentrated to remove the solvent andrecrystallized twice from methanol, filtering the hot, yellow solutionthru a sintered glass funnel and concentrating the filtrate to a volumeof about 200 ml., cooling, collecting the solid and drying it in vacuoat 80° C. to yield 6.1 g. of5-(4-aminophenyl)1,2-dihydro-2-oxonicotinonitrile as itsmonomethanesulfonate, m.p. 252°-260° C.

A-5. 1,2-Dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile--Amixture containing 100 g. of 97% 3-(4-methoxyphenyl)propan-2-one, 94.2ml. of dimethylformamide dimethyl acetal and 500 ml. ofdimethylformamide was stirred at room temperature for over 17 hours andthen on a steam bath for 2 hours. There was then added 23.6 ml. ofdimethylformamide dimethyl acetal followed by stirring at roomtemperature for about 75 minutes and then on a steam bath for about 2and 1/2 hours. To the partially cooled solution containing4-dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one was added 79.8 g. ofsodium methoxide and 74.5 g. of cyanoacetamide and the resulting mixturewas heated on a steam bath with stirring for about 12 hours. Thereaction mixture was then diluted with about 1.5 liters of water and theresulting suspension was acidified with acetic acid. The separated solidwas collected and recrystallized from dimethylformamidewater to yield116.8 g. of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile, m.p.253°-255° C. A sample of this material was further purified byrecrystallizing successively from methanol and acetic acid-water anddrying at 90°-95° C. in vacuo for over 24 hours to yield said product,m.p. 258°-259° C.

A-6. 1,2-Dihydro-5-(4-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile, m.p.275°-276° C. with decomposition, was prepared following the proceduredescribed in Example A-2 using 12.0 g. of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile, 36.8 g.of lithium iodide and 120 ml. of collidine.

Following the procedure described in Example A-1 but using in place of3-dimethylamino-2-(4-methoxyphenyl)-2-propenal a molar equivalentquantity of the appropriate3-dimethylamino-2-(substituted-phenyl)-2-propenal, it is contemplatedthat the corresponding1,2-dihydro-2-oxo-5-(substituted-phenyl)nicotinonitriles of Examples A-7through A-11 can be obtained

A-7. 1,2-Dihydro-5-(3-methoxyphenyl)-2-oxonicotinonitrile.

A-8. 1,2-Dihydro-5-(3,4-dimethoxyphenyl)-2-oxonicotinonitrile.

A-9. 1,2-Dihydro-5-(3-nitrophenyl)-2-oxonicotinonitrile.

A-10. 1,2-Dihydro-5-(3,4-dinitrophenyl)-2-oxonicotinonitrile.

A-11. 1,2-Dihydro-5-(4-methoxy-3-nitrophenyl)-2-oxonicotinonitrile.

The intermediate 3-dimethylamino-2-(substituted-phenyl)-2-propenals usedin Examples A-7 through A-11 are either known or are readily preparedfrom known compounds by conventional means, e.g., by reacting anα-(substituted-phenyl)-acetic acid with the reaction product obtained byreacting dimethylformamide with a phosphorus oxyhalide, preferably theoxychloride or oxybromide, as illustrated in the following paragraph forthe intermediate used to prepare Example A-8.

The intermediate 2-(3,4-dimethoxyphenyl)-3-dimethylamino-2-propenal wasprepared as follows: To a chilled 1260 ml. portion of dimethylformamidewas added dropwise 230 ml. of phosphorus oxychloride followed byaddition of 196 g. of α-(3,4-dimethoxyphenyl)acetic acid. The reactionmixture was heated at about 70° C. on a steam bath for 3 hours, allowedto cool and then concentrated in vacuo to remove the solvent and excessvolatile reactants. The resulting product was used directly in the aboveprocedure to prepare Example A-8.

Following the procedure described in Example A-2 or A-4 but using inplace of 1,2-dihydro-5-(4-methoxyphenyl or4-nitrophenyl)-2-oxonicotinonitrile a molar equivalent quantity of theappropriate 1,2-dihydro-5-(substituted-phenyl)-2-oxonicotinonitrile, itis contemplated that the corresponding compounds of Examples A-12through A-16 can be obtained.

A-12. 1,2-Dihydro-5-(3-hydroxyphenyl)-2-oxonicotinonitrile, m.p.283°-287° C., using the corresponding 5-(3-methoxyphenyl) compound andthe procedure of Example A 2.

A-13. 1,2-Dihydro-5-(3,4-dihydroxyphenyl)-2-oxonicotinonitrile using thecorresponding 5-(3,4-dimethoxyphenyl) compound and the procedure ofExample A-2.

A-14. 1,2-Dihydro 5-(4-methoxy-3-aminophenyl)-2-oxonicotinonitrile usingthe corresponding 5-(4-methoxy-3-nitrophenyl) compound and the procedureof Example A-4.

A-15. 1,2-Dihydro-5-(3-aminophenyl)-2-oxonicotinonitrile using thecorresponding 5-(3-nitrophenyl) compound and the procedure of ExampleA-4.

A-16. 1,2-Dihydro-5-(3,4-diaminophenyl)-2-oxonicotinonitrile thecorresponding 5-(3,4-dinitrophenyl) compound and using the procedure ofExample A-4.

Following the procedure described in Example A-5 but using in place of3-(4-methoxyphenyl)propan-2-one a molar equivalent quantity of theappropriate 3-(substituted-phenyl)propan-2-one or substituted-benzyllower-alkyl ketone, it is contemplated that the corresponding1,2-dihydro-2-oxo-5-(substituted-phenyl)-6-methyl(orlower-alkyl)-nicotinonitriles of Examples A-17 to A-20 can be obtained

A-17. 1,2-Dihydro-5-(3-methoxyphenyl)-6-methyl-2-oxonicotinonitrile,m.p. 247°-250° C., starting with 3-(3-methoxyphenyl)propan-2-one.

A-18. 1,2-Dihydro-5-(3,4-dimethoxyphenyl)-6-methyl-2-oxonicotinonitrile,m.p. 262°-263° C., starting with 3-(3,4-dimethoxyphenyl)propan-2-one via4-dimethylamino-3-(3,4-dimethoxyphenyl)-3-buten-2-one, m.p. 94°-95.5° C.(prepared as in Example A-5).

A-19. 1,2-Dihydro-5-(4-nitrophenyl)-6-methyl-2-oxonicotinonitrile,starting with 3-(4-nitrophenyl)propan-2-one.

A-20. 1,2-Dihydro-5-(4-methoxyphenyl)-6-ethyl-2-oxonicotinonitrile,starting with 1-(4-methoxyphenyl)butan-2-one.

A-21.1,2-Dihydro-5-(4-methoxy-3-nitrophenyl)-6-methyl-2-oxonicotinonitrile,m.p. >300° C., starting with 3-(4-methoxy-3-nitrophenyl)propan-2-one.Alternatively,1,2-dihydro-5-(4-methoxy-3-nitrophenyl)-6-methyl-2-oxonicotinonitrilewas prepared by nitrating1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile by heatingit with concentrated nitric acid in acetic acid on a steam bath for twohours and then pouring the reaction mixture into water and collectingthe product.

Following the procedure described in Example A-2 or A-4 but using inplace of 1,2-dihydro-5-(4-methoxyphenyl or4-nitrophenyl)-2-oxonicotinonitrile a molar equivalent quantity of theappropriate1,2-dihydro-5-(substituted-phenyl)-6-(lower-alkyl)-2-oxonicotinonitrile,it is contemplated that the corresponding compounds of Examples A-22through A-27 can be obtained.

A-22. 1,2-Dihydro-5-(3-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile,using 1,2-dihyro-5-(3-methoxyphenyl)-6-methyl-2-oxonicotinonitrile andthe procedure of Example A-2.

A-23. 1,2-Dihydro-5-(3,4-dihydroxyphenyl)-6-methyl-2-oxonicotinonitrile,m.p. 267° C. (chars), using1,2-dihydro-5-(3,4-dimethoxyphenyl)-6-methyl-2-oxonicotinonitrile andthe procedure of Example A-2.

A-24. 1,2-Dihydro-5-(4-aminophenyl)-6-methyl-2-oxonicotinonitrile, using1,2-dihydro-5-(4-nitrophenyl)-6-methyl-2-oxonicotinonitrile and theprocedure of Example A-4.

A-25. 1,2-Dihydro-5-(4-hydroxyphenyl)-6-ethyl-2-oxonicotinonitrile,using 1,2-dihydro-5-(4-methoxyphenyl)-6-ethyl-2-oxonicotinonitrile andthe procedure of Example A-2.

A-26.1,2-Dihydro-5-(4-hydroxy-3-nitrophenyl)-6-methyl-2-oxonicotinonitrile,m.p. 290°-293° C., using1,2-dihydro-5-(4-methoxy-3-nitrophenyl)-6-methyl-2-oxonicotinonitrileand the procedure of Example A-2.

A-27.1,2-Dihydro-5-(3-amino-4-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile,m.p. >300° C. as its (1:1) phosphate (H₃ PO₄) salt, using1,2-dihydro-5-(4-hydroxy-3-nitrophenyl)-6-methyl-2-oxonicotnonitrile andthe procedure of Example A-4 or using1,2-dihydro-5-(4-methoxy-3-aminophenyl)-6-methyl-2-oxonicotinonitrileand the procedure of Example A-2.

Following the procedure described in Example A-5 but using in place ofcyanoacetamide a molar equivalent quantity of the appropriate N-R₁-cyanoacetamide, it is contemplated that the corresponding 1-R₁-1,2-dihydro5-(4-methoxyphenyl)-6-R-2-oxonicotinonitrile of ExamplesA-28 and A-29 can be obtained.

A-28. 1,2-Dihydro-5-(4-methoxyphenyl)-1,6-dimethyl-2-oxonicotinonitrile,using N-methylcyanoacetamide.

A-29.1,2-Dihydro-1-(2-hydroxyethyl)-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile,using N-(2-hydroxyethyl)cyanoacetamide.

Following the procedure described in Example A-2 but using in place of1,2-dihydro-5-(4-methoxyphenyl)2-oxonicotinonitrile a molar equivalentquantity of the appropriate 1-R₁-1,2-dihydro-5-(4-methoxyphenyl)-6-(lower-alkyl)-2-oxonicotinonitrile,it is contemplated that the corresponding compounds of Examples A-31 andA-32 can be obtained.

A-31. 1,2-Dihydro-5-(4-hydroxyphenyl)-1,6-dimethyl-2-oxonicotinonitrile.

A-32.1,2-Dihydro-1-(2-hydroxyethyl)-5-(4-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile.

B. 1-R₁ -5-(SUBSTITUTED-PHENYL)-6-R-2(1H)-PYRIDINONES--

B-1. 5-(4-Hydroxyphenyl)-6-methyl-2(1H)-pyridinone-- A mixturecontaining 20 g. of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile and 200ml. of 85% phosphoric acid was refluxed with stirring for about 15hours, allowed to cool and then poured onto ice. The aqueous mixture wasmade alkaline with concentrated ammonium hydroxide and the resultingwhite precipitate was collected, washed with water and dried in vacuo at60° C. This material was purified by first recrystallizing it fromdimethylformamide-water and then taking up the recrystallized materialin about 150 ml. of 10% aqueous sodium hydroxide solution, filtering offa small quantity of undissolved white material and acidifying thefiltrate with acetic acid whereupon a white precipitate separated. Theprecipitate was collected, dried in vacuo at 60° C. to yield 11 g. of5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone, m.p. 275°-276° C.

5-(4-Hydroxyphenyl)-6-methyl-2(1H}-pyridinone also was produced byfollowing the above procedure of Example B-1 using in place of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile a molarequivalent quantity of1,2-dihydro-5-(4-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile.

B-2. 5-(3-Hydroxyphenyl)-6-methyl-2(1H)-pyridinone, m.p. 285°-288° C.,was obtained following the procedure described in example B-1 using1,2-dihydro-5-(3-methoxyphenyl)-6-methyl-2-oxonicotinonitrile andseveral recrystallizations of the product from 95% ethanol.

5-(3-Hydroxyphenyl)-6-methyl-2(1H)-pyridinone also is produced byfollowing the above procedure of Example B-2 using in place of1,2-dihydro-5-(3-methoxyphenyl)-6-methyl-2-oxonicotinonitrile a molarequivalent quantity of1,2-dihydro-5-(3-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile.

B-3. 5-(4-Hydroxyphenyl)-2(1H)-pyridinone, m.p. >300° C., was preparedfollowing the procedure described in Example B-1 using in place of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile a molarequivalent quantity of1,2-dihydro-5-(4-methoxyphenyl)-2-oxonicotinonitrile.

B-4. 5-(3-Hydroxyphenyl)-2(1H)-pyridinone as its hydrate (4:1), m.p.246°-248° C. with decomposition, was prepared following the proceduredescribed in Example B-1 using in place of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile a molarequivalent quantity of1,2-dihydro-5-(3-methoxyphenyl)-2-oxonicotinonitrile.

Following the procedure described in Example B-1 but using in place of1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile a molarequivalent quantity of the appropriate1,2-dihydro-5-(3-R'-4-R"-phenyl)-6-R-2-oxonicotinonitrile, it iscontemplated that there can be obtained the following5-(3-R'-4-R"-phenyl)-6-R-2-(1H)-pyridinones of Examples B-5 thru B-14.

B-5. 5-(4-Aminophenyl)-2-(1H)-pyridinone from5-(4-aminopheny)-1,2-dihydro-2-oxonicotinonitrile.

B-6. 5-(3,4-Dihydroxyphenyl)-2(1H)-pyridinone from1,2-dihydro-5-(3,4-dimethoxyphenyl)-2-oxonicotinonitrile or1,2-dihydro-5-(3,4-dihydroxyphenyl)-2-oxonicotinonitrile.

B-7. 5-(4-Hydroxy-3-aminophenyl)-2(1H)-pyridinone from1,2-dihydro-5-(4-methoxy-3-aminophenyl)-2-oxonicotinonitrile or1,2-dihydro-5-(4-hydroxy-3-aminophenyl)-2-oxonicotinonitrile.

B-8. 5-(3-Aminophenyl)-2(1H)-pyridinone from1,2-dihydro-5-(3-aminophenyl)-2-oxonicotinonitrile.

B-9. 5-(3,4-Diaminophenyl)-2(1H)-pyridinone from1,2-dihydro-5-(3,4-diaminophenyl)-2-oxonicotinonitrile.

B-10. 5-(3,4-Dihydroxyphenyl)-6-methyl-2(1H)-pyridinone, m.p. 261°-262°C., from1,2-dihydro-5-(3,4-dimethoxyphenyl)-6-methyl-2-oxonicotinonitrile or1,2-dihydro-5-(3,4-dihydroxyphenyl)-6-methyl-2-oxonicotinonitrile.

B-11. 5-(4-Hydroxyphenyl)-6-ethyl-2(1H)-pyridinone from1,2-dihydro-5-(4-methoxyphenyl)-6-ethyl-2-oxonicotinonitrile or1,2-dihydro-5-(4-hydroxyphenyl)-6-ethyl-2oxonicotinonitrile.

B-12. 5-(4-Aminophenyl)-6-methyl-2(1H)-pyridinone from1,2-dihydro-5-(4-aminophenyl)-6-methyl-2-oxonicotinonitrile.

B-13. 5-(4-Hydroxyphenyl)-1,6-dimethyl-2(1H)pyridinone from1,2-dihydro-5-(4-methoxyphenyl)-1,6-dimethyl-2-oxonicotinonitrile or1,2-dihydro-5-(4-hydroxyphenyl)-1,6-dimethyl-2 oxonicotinonitrile.

B-14. 1-(2-Hydroxyethyl)-5-(4-hydroxyphenyl)-6-methyl-2(1H)pyridinonefrom1,2-dihydro-1-(2-hydroxyethyl)-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrileor1,2-dihydro-1-(2-hydroxyethyl)-5-(4-hydroxyphenyl)-6-methyl-2-oxonicotinonitrile.

B-15. 5-(4-Hydroxy-3-nitrophenyl)-6-methyl-2(1H)-pyridinone -- A mixturecontaining 2.0 g. of 5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone and25 ml. of acetic acid was heated with stirring on a steam bath to obtaina solution. To the hot solution, no longer heated on a steam bath, wasadded dropwise with stirring a solution containing 0.42 ml. of 90%nitric acid in 4.2 ml. of acetic acid. The resulting reaction mixturewas allowed to stand for thirty minutes and to it was then added 40 mlof water. The resulting precipitate was collected, washed successivelywith water and acetone and dried in vacuo at 50° C. to yield 1.41 g.(57% yield) of 5-(4-hydroxy-3-nitrophenyl)-6-methyl-2(1H)-pyridinone,m.p. 260°-262° C.; this material was used directly in Example B-16. Inanother run, this compound was recrystallized from dimethylformamide,then dissolved in 10% aqueous sodium hydroxide solution, reprecipitatedwith 6N hydrochloric acid, collected, washed successively with water andacetone and dried in vacuo at 50° C. to produce (78% recovery onrecrystallization)5-(4-hydroxy-3-nitrophenyl)-6-methyl-2(1H)-pyridinone, m.p. 262°-264° C.

B-16. 5-(3-Amino-4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone -- A mixturecontaining 8.8 g. of5-(4-hydroxy-3-nitrophenyl)-6-methyl-2(1H)-pyridinone, 1200 ml. ofethanol and 0.9 g. of 10% palladium-on-charcoal was shaken with hydrogenunder pressure at room temperature under catalytic hydrogenationconditions until tlc analysis showed that the starting material wasconsumed. The reaction mixture was filtered and the filtrate wasevaporated in vacuo to remove the solvent. The residue was dissolved indimethylformamide and the product was precipitated by addition of ether.The precipitate was collected, washed successively with water andacetone and dried in vacuo at 50° C. to yield 6.2 g. (60% yield) of5-(3-amino-4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone, m.p. 279°-283° C.This product was placed in 125 ml. of methanol, the mixture acidifiedwith hydrogen chloride in ether and the product precipitated as itshydrochloride salt by addition of ether. The salt was dissolved inwater, the solution treated with decolorizing charcoal and filtered. Theproduct in free base form was precipitated by adding 1N aqueous sodiumhydroxide solution to the filtrate to neutral pH. The precipitate wascollected, washed successively with water and acetone and dried in vacuoat 50° C. to yield 2.3 g. (30%) of5-(3-amino-4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone, m.p. 282°-283° C.

The utility of the compounds of formulas I and II as cardiotonic agentsis demonstrated by their effectiveness in standard pharmacological testprocedures, for example, in causing a significant increase incontractile force of the isolated cat or guinea pig atria and papillarymuscle and/or in causing a significant increase in the cardiaccontractile force in the anesthetized dog with low or minimal changes inheart rate and blood pressure. Detailed descriptions of these testprocedures appear in U.S. Pat. No. 4,072,746, issued Feb. 7, 1980.

When tested by said isolated cat or guinea pig atria and papillarymuscle procedure, the compounds of formula I or II at doses of 3, 10,30, and/or 100 μg/ml., were found to cause significant increases, thatis, greater than 25% (cat) or 30% (g. pig) in papillary muscle force andsignificant increases, that is, greater than 25% (cat) or 30% (g. pig)in right atrial force, while causing a lower percentage increase (aboutone-half or less than the percentage increase in right atrial force orpapillary muscle force) in right atrial rate. Because of the lowercontrol active tensions of guinea pig tissues, the percent change fromcontrol values of both rate and force responses is elevated slightly,i.e., 5%. Thus, whereas cardiotonic activity is ascertained with apapillary muscle force or right atrial force increase of 26% and greaterin the cat test, corresponding activity in the guinea pig test isdesignated with a papillary muscle force or right atrial force increaseof 31% or greater. The compounds of formula I, in particular, thosewhere R is methyl, are markedly more active as cardiotonics comparedwith the corresponding compounds where R is hydrogen. For example, thecompound of Example B-1, namely,5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone, when tested by said catatria and papillary muscle procedure was found to cause papillary muscleand right atrial force increases of 86% and 77% when tested at 10μg./ml. compared with corresponding respective papillary muscle andright atrial force increases of 97% and 53% found for prior art5-(4-hydroxyphenyl)-2(1H)-pyridinone, the compound of Example B-3, whentested by the same procedure at 100 μg./ml., that is, at ten times thedose level. Similarly, the compound of Example B-2, namely,5-(3-hydroxyphenyl)-6-methyl-2(1H)-pyridinone, when tested by saidguinea pig atria and papillary muscle procedure was found to causepapillary muscle and right atrial force increases of 143% and 79%respectively at 10 μg./ml. compared with corresponding increases of 78%and 86% for 5-(3-hydroxyphenyl)-2(1H)-pyridinone, the compound ofExample B-4, when tested by the same procedure at 100 μg./ml., that is,at ten times the dose level. Other illustrative guinea pig papillarymuscle and right atrial rate increases for compounds of the inventionare: 92% and 38% at 10 μg./ml. for Example B-16; 170% and 300% at 30μg./ml. and 102% and 123% at 10 μg./ml. for Example B-10; and, 139% and73% at 10 μg./ml. and 65% and 68% at 3 μg/ml for Example B-15.

When tested by said anesthetized dog procedure, the compounds offormulas I and II or pharmaceutically-acceptable acid-addition saltsthereof where at least one of R' and R" is amino at doses of 0.3, 1.0,3.0 and/or 10 mg./kg. administered intravenously were found to causesignificant increases, that is, 25% or greater, in cardiac contractileforce or cardiac contractility with lower changes in heart rate andblood pressure. For example, when tested at 0.10, 0.3 and/or 1.0 mg./kg.by this procedure the compounds of Examples B-1, B-2 and B-15 were foundto cause increases of 50% and greater in contractile force and lowerchanges in heart rate and blood pressure.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier and, as the activecomponent thereof, a cardiotonically effective amount of the compound offormula I or II. The invention also includes within its scope the methodfor increasing cardiac contractility in a patient requiring suchtreatment which comprises administering to such patient said cardiotoniccomposition providing a cardiotonically effective amount of saidcompound of formula I or II. In clinical practice said compound willnormally be administered orally or parenterally in a wide variety ofdosage forms.

Solid compositions for oral admininstration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions canalso contain additional substances other than inert diluents, e.g.,lubricating agents, such a magnesium stearate, talc and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water andliquid paraffin. Besides inert diluents such compositions can alsocontain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueousorganic and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilising, preserving,wetting, emulsifying and dispersing agents.

They can be sterilized, for example, by filtration through abacteria-retaining filter, by incorporation of sterilising agents in thecompositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active component in the said composition and methodfor increasing cardiac contractility can be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing his best judgement on the patient's behalf.

We claim:
 1. The process which comprises refluxing a 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile, where R₁ ishydrogen, lower-alkyl or lower-hydroxyalkyl, R is hydrogen orlower-alkyl, R' is hydrogen, hydroxy, methoxy or amino and R" ishydroxy, methoxy or hydrogen, or where R' is nitro when R" is hydroxy ormethoxy, with a multi-molar excess of 85% phosphoric acid to produce1-R₁ -5-(3-R'-4R"-phenyl)-6-R-2(1H)-pyridinone, where R₁ and R have themeanings given above, R' is hydrogen, hydroxy or amino and R" is hydroxyor hydrogen, at least one of R' and R" being hydroxy, or where R' isnitro when R" is hydroxy.
 2. The process according to claim 1 whichcomprises refluxing a 1-R₁-1,2-dihydro-2-oxo-5-(3-R'-4-R"-phenyl)-6-R-nicotinonitrile, where R₁ ishydrogen, lower-alkyl or lower-hydroxyalkyl, R is hydrogen orlower-alkyl, R'is hydrogen, methoxy or amino and R" is methoxy orhydrogen, at least one of R' AND R" being methoxy, or where R' is nitrowhen R" is methoxy, with a multi-molar excess of 85% phosphoric acid toproduce 1-R₁ -5-(3-R'-4-R"-phenyl)-6-R-2(1H)-pyridinone, where R₁ and Rhave the meanings given above, R' is hydrogen, hydroxy or amino and R"is hydroxy or hydrogen, at least one of R' and R" being hydroxy, orwhere R' is nitro when R" is hydroxy.
 3. The process according to claim1 using the nicotinonitrile where R₁ is hydrogen, R is methyl or ethyl,R' is hydrogen, methoxy or amino and R" is methoxy or hydrogen, at leastone of R' and R" being methoxy.
 4. The process according to claim 3using 1,2-dihydro-5-(4-methoxyphenyl)-6-methyl-2-oxonicotinonitrile toproduce 5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone.
 5. The processaccording to claim 3 using1,2-dihydro-5-(3methoxyphenyl)-6-methyl-2-oxo-nicotinonitrile to produce5-(3-hydroxyphenyl)-6-methyl-2(1H)-pyridinone.
 6. The process accordingto claim 3 using1,2-dihydro-5-(3,4-dimethoxyphenyl)-6-methyl-2-oxo-nicotinonitrile toproduce 5-(3,4-dihydroxyphenyl)-6-methyl-2(1H)-pyridinone.
 7. Theprocess according to claim 2 using1,2-dihydro-5-(4-methoxy-3-nitrophenyl)-6-methyl-2-oxonicotinonitrile toproduce 5-(4-hydroxy-3-nitrophenyl)-6-methyl-2(1H)-pyridinone.
 8. Theprocess according to claim 3 using5-(3-amino-4-methoxyphenyl)-1,2-dihydro-6-methyl-2-oxonicotinonitrile toproduce 5-(3-amino-4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone.